Fragile X Syndrome (FXS) is the most common form of inherited intellectual disabilities. The primary cause is transcriptional silencing of the FMR1 gene, which encodes the Fragile X Mental Retardation Protein (FMRP). Patients with Fragile X exhibit a range of neurologic defects including impaired cognition and social interactions, delayed speech, hyperactivity, emotional lability, attentional deficits, seizures, and autistic-lik behaviors. The onset of symptoms occurs by the age of 3, and usually requires extensive support for the lifetime of the afflicted. An estimated one in every 3000 children born in the US develops Fragile X Syndrome. An effective treatment for the cognitive and social interaction deficits associated with Fragile X remains an unmet medical need. A neuroanatomical hallmark of Fragile X is an overabundance of long, thin dendritic spines. However, the molecular mechanisms linking loss of FMRP to aberrant spine morphology remains unclear. Cofilin is an actin depolymerizing factor and central regulator of apoptosis, activity-dependent synaptic plasticity, and dendritic spine morphology. Our recent discovery that cofilin signaling is dysregulated in a mouse model of Fragile X and is linked to aberrant spine morphology implicates dysregulation of the cofilin pathway in the etiology of intellectual disabilities. Emerging evidence indicates that cofilin signaling is under the control the mTOR Complex 2 (mTORC2) pathway. mTORC2 is a macromolecular signaling complex comprised of mTOR, rapamycin-insensitive companion of mTOR (Rictor), GL, and mSIN1 and is a central regulator of the cytoskeleton. In addition, mTORC2 regulates embryonic development, actin polymerization and dendritic spine structure important to synaptic efficacy and the consolidation of long-term memory. The overall goal of the proposed research is to examine a possible causal role for mTORC2 as a central regulator of cofilin signaling and spine abnormalities in Fragile X and establish components of the mTORC2 complex as novel therapeutic targets for amelioration of this devastating human condition. The underlying hypothesis is that overactivated mTORC2 signaling is causally related to reduced cofilin activity and abnormalities in spine morphology in the Fragile X mouse. The overall strategy will be to examine a causal relation between elevated mTORC2 signaling and synaptic dysfunction in the somatosensory cortex of the Fragile X mouse. Experiments will 1) identify signaling pathways downstream of mTORC2 that are dysregulated in the somatosensory cortex of Fragile X mice; and 2) examine the ability of genetic reduction of Rictor to rescue signaling and spine abnormalities in Fragile X mice. This will document a causal relation between mTORC2 activity, cofilin signaling, and spine defects observed in Fragile X. We believe these studies will unlock doors for our understanding of the synaptic phenotype not only of Fragile X Syndrome, but of other ASDs.